Interception of host fatty acid metabolism by mycobacteria under hypoxia to suppress anti-TB immunity

One striking characteristic of mycobacteria is its formation of hypoxic granuloma for persistent infection in which immunity contains, but fails to eliminate the bacteria. Though host-derived fatty acids are usually favored for mycobacteria as nutrient resources, whether and how mycobacteria modulate host fatty acid metabolism for the formation of granuloma remains unknown. Here, we report that mycobacteria under hypoxia dramatically secrets a protein Rv0859, which is also enriched in tuberculous granuloma. Rv0859 acts as an acetyltransferase that converts host acetyl-CoA to acetoacetyl-CoA. The reduced acetyl-CoA level suppresses H3K9Ac-mediated expression of Il6, thus promoting the progression of granuloma and mycobacteria growth. Moreover, supplementation of acetate enhances the acetyl-CoA level and inhibits the formation of granuloma and mycobacteria growth. These findings reveal an unexpected mechanism that mycobacteria under hypoxic dilemma exploits to suppress anti-TB immunity for persistent infection, and provide a host-directed therapy strategy for latent TB infection by targeting the interface between hypoxia-induced mycobacterial protein and fatty acid metabolic pathway.